Previous molecular epidemiology studies on head and neck cancer have examined one to several single nucleotide polymorphisms (SNPs) among several hundred cases and controls, focusing on sequence variants in carcinogen metabolism and DNA repair genes. The inconsistent results observed across these studies may be due to: i) low statistical power in detecting modest risk sequence variants, ii) false positive results, iii) publication bias, and iv) a moderate prior probability that each SNP individually confers substantial increase in risk. Furthermore, examining the main effects of one or few modest risk sequence variants is an overly simplified approach, when considering that carcinogenesis is highly complex, with numerous genes acting on multiple pathways plus their interactions with environmental factors. Moving from single marker analyses to tests of multiple SNPs and gene-environment interactions is necessary, but requires considerable sample size and statistical power. Therefore, we propose to conduct pooled analyses within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, a recently established collaboration of research groups leading large molecular epidemiology studies of head and neck cancer. We will combine data from 7 US studies and 3 European studies on more than 5000 case-control pairs for 18 SNPs. Our specific aims are: 1) to conduct pooled analysis on 11 SNPs in genes that encode carcinogen metabolizing enzymes and the risk of head and neck cancer, 2) to conduct pooled analysis on 7 SNPs in DNA repair genes, 3) to apply novel statistical methods including the assessment of false positive report probability and hierarchical modeling approaches to address the possibility of false positive results and to incorporate prior knowledge on these genes. The hypotheses of interest are: a) SNPs in the carcinogen metabolism and DNA repair genes confer an increased risk of head and neck cancer, and the magnitude of effect of each SNP is modest b) inheritance of multiple alleles at these loci confer a higher risk of head and neck cancer, c) there are multiple gene-gene and gene-environment interactions among these sequence variants and environmental factors. We believe that our proposed analyses is a cost effective approach in generating data for a large head and neck cancer study, that will address the limitation of previous studies and provide a clearer picture of the role of these SNPs in head and neck cancer carcinogenesis.